Is TCF4 p.Ser312= (c.936C>T) pathogenic?

TCF4 p.Ser312= (c.936C>T) is classified Benign/Likely benign in TCF4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-04-01). Ultra-rare (popmax 0.0703%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TCF4 p.Ser312= (c.936C>T)?

TCF4 p.Ser312= (c.936C>T) is associated with Inborn genetic diseases, Pitt-Hopkins syndrome (ClinVar).

How common is TCF4 p.Ser312= (c.936C>T) in the general population?

TCF4 p.Ser312= (c.936C>T) is ultra-rare (popmax 0.0703%, nfe) (gnomAD).

TCF4 p.Ser312=

c.936C>T · rs368270265 · VCV139405

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0703%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.35	GERP -3, phastCons 0.93
Overall
CADD	10.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0703% European (non-Finnish) · 830/1,179,840 alleles

Filtering AF 0.0663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0647%

Overall 0.0577% 931/1,613,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.115%	870
European (non-Finnish)grpmax	0.0703%	1,421
Remaining individualsnot grpmax-eligible	0.0672%	1,488
Admixed American	0.0183%	5,455
African / African-American	0.012%	8,333
South Asian	0.00549%	18,216

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TCF4
Protein: p.Ser312=
Coding: c.936C>T
MANE Select: NM_001083962
dbSNP: rs368270265
Type: single nucleotide variant
Location: chr18:55261520 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 312: the 'disordered' region

Full TCF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Pitt-Hopkins syndrome

Similar variants

TCF4 p.Ser312Asn Uncertain significance ★ ⚠ same residue
TCF4 p.Arg576Gln Pathogenic ★★★ same condition
TCF4 p.Arg578His Pathogenic ★★★ same condition
TCF4 p.Arg580Gln Pathogenic ★★★ same condition
TCF4 p.Arg580Trp Pathogenic ★★★ same condition
TCF4 p.Arg582Cys Likely pathogenic ★★★ same condition
TCF4 p.Gly496Cys Likely pathogenic ★★★ ⚠ same condition
TCF4 p.Gly592Ser Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tcf4-p-ser312 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown